Mild traumatic brain injuries (mTBIs) are a prevalent form of injury that can result in persistent neurological impairments. Microglial activation has become increasingly recognized as a key process regulating the pathology of white matter in a wide range of brain injury and disease contexts. As white matter damage is known to be a major contributor to the impairments that follow mTBI, microglia have rightfully become a common target of investigation for the development of mTBI therapies and biomarkers. Recent work has demonstrated that the efficacy of microglial manipulation as a therapeutic intervention following injury or disease is highly time-sensitive, emphasizing the importance of advancing our understanding of the dynamics of post-mTBI microglial activation from onset to resolution. Current reporting of microglial activation in experimental studies of mTBI is non-standardized, which has limited our ability to identify concrete patterns of post-mTBI microglial activation over time. In this review, we examine preclinical studies of mTBI that report on microglial activation in white matter regions to summarize our current understanding of these patterns. Specifically, we summarize timecourses of post-mTBI microglial activation in white matter regions of the brain, identify factors that influence this activation, examine the temporal relationship between microglial activation and other post-mTBI assessments, and compare the relative sensitivities of various methods for detecting microglial activation. While the lack of replicated experimental conditions has limited the extent of conclusions that can confidently be drawn, we find that microglia are activated over a wide range of timecourses following mTBI and that microglial activation is a long-lasting outcome of mTBI that may resolve after most typical post-mTBI assessments, with the exception of those measuring oligodendrocyte lineage cell integrity. We identify several understudied parameters of post-mTBI microglial activation in white matter, such as the inclusion of female subjects. This review summarizes our current understanding of the progression of microglial activation in white matter structures following experimental mTBI and offers suggestions for important future research directions.
The ordering of experimental groups in Fig. 3 reveals a general trend of longer timepoints assessed for studies which examined a greater number of mTBIs. Assessments of microglial activation that showed no significant differences relative to shams appear to disproportionately occur in the lower half of Fig. 3, suggesting that a greater number of mTBIs may be associated with a longer timecourse of microglial activation.
Lasting Longer Dr Sy Silverberg Pdf 51
Several studies report microglial activation at relatively chronic phases of the injury, ranging from 2 weeks post-final-injury to 1 year post-final-injury. These studies include groups 29a ([46]; 20 weight drop injuries to mice spaced 1 to 3 days apart; activation lasting at least 90 dpfi), 21b and 21c ([35]; 5 controlled piston-driven impacts to mice spaced 1 or 2 days apart; activation lasting at least 70 dpfi), 19a ([47]; 4 fluid pulse injuries to rats spaced 7 days apart; activation lasting at least 90 dpfi), 17a-c ([43]; 2 weight drop injuries to rats spaced 1 day apart; activation lasting at least 90 dpfi), 23a ([48]; 5 controlled piston-driven impacts to mice spaced 2 days apart; activation lasting at least 270 dpfi), 18a ([49]; 3 weight drop injuries to mice; activation lasting at least 60 dpfi), 20a and 20b ([50]; 4 controlled piston-driven impacts given to mice; activation lasting at least 180 dpfi), 25a and 25b ([51]; 1 or 5 controlled piston-driven impacts spaced 2 days apart; activation lasting at least 360 dpfi), 26a ([52]; 5 controlled piston-driven impacts to mice spaced 2 days apart; activation lasting at between 90 and 180 dpfi), 08a ([53]; 1 controlled piston-driven impact to ferrets; activation lasting at least 112 dpfi), 09a and 09b ([54]; 1 controlled piston-driven impact to mice; activation lasting at least 30 dpfi), 16a ([39]; 2 controlled piston-driven impacts to mice spaced 1 day apart; activation lasting at least 49 dpfi), 30a ([55]; 30 controlled piston-driven impacts to mice spaced 1 to 3 days apart; activation lasting at least 365 dpfi), and 27a ([41]; 5 controlled piston-driven impacts spaced 1 day apart; activation lasting at least 42 dpfi). For the groups in which the final timepoint assessed showed increased microglial activation in the white matter, it is unknown whether or not that activation will eventually resolve.
The limitations of symptom-based guidelines for mTBI patients returning to high-risk activity are emphasized by the majority of detectable behavioural deficits in experimental groups resolving prior to the end of microglial activation in the white matter. A patient with persisting neuroinflammation that sustains a subsequent mTBI may experience longer lasting and more serious impairment as a consequence [70]. Though the behavioural methods tallied in this review are not perfectly representative of the post-mTBI deficits that humans experience, the possibility of incomplete brain recovery persisting beyond the apparent resolution of symptoms for any patient of mTBI may be a valid generalization.
Oligodendrocyte lineage marker disruption was found to persist after the resolution of microglial activation. Given the substantial body of evidence suggesting that white matter impairment is one of the strongest correlates of impairment following mTBI [6,7,8, 77], we interpret this finding as support for the possibility that microglia contribute to prolonged impairment following mTBI by mediating lasting damage to white matter structures of the brain. This damage may be caused during periods of overactivation but persist well after microglia have returned to homeostatic levels. Though microglia also function to repair white matter pathology following injury, the incomplete recovery of oligodendrocyte lineage cells to a homeostatic transcriptional signature could be indicative of those repair processes ending prematurely. This persistent white matter damage may be too subtle to detect through traditional experimental behavioural tests but may compound after additional injuries into more serious impairment. In the clinical context, this may be analogous to slight alterations in cognition or behaviour that are not easily observed by current techniques in symptom assessment.
As a consequence of including studies that may have been statistically underpowered (see Additional File 2), this review has a risk of misinterpreting instances where one group has a lower magnitude but longer lasting period of microglial activation relative to another group as a situation in which that second group has the longer lasting activation. This review also has a risk of mischaracterizing the relative order of the resolution of different post-mTBI changes which used assessment methods of different sensitivities.
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